This Program explores the use of somatic gene therapy to augment the host immune response to cancer. The various projects will genetically modify effector cells to improve their anti-tumor activity or modify tumor cells to improve immunogenicity. Basic and preclinical investigations will explore methods of optimal gene transfer into T lymphocytes, macrophages and tumor cells using retroviral and adeno-associated virus vectors. Mechanistic studies will focus on ways to improve anti-tumor activity of tumor-infiltrating lymphocytes (TIL) and macrophages using cytokine genes such as IL-7 and IL-6 and cytotoxin genes such as perforin and defensin. Efforts to improve tumor immunogenicity will employ cytokine gene transduction or modulation of MHC expression by altering oncogene expression. The goal will be to develop genetically- engineered vaccines capable of stimulating tumor immunity or generating immune lymphocytes in draining lymph nodes suitable for adoptive immunotherapy trials. Preclinical animal models, including the use of SCID/hu mice, will study interactions between genetically modified human effector and tumor cells in vivo. Clinical trials are proposed for the gene therapy of melanoma, renal cancer, leukemia and neuroblastoma that directly translate basic and preclinical efforts. In summary, we plan a comprehensive basic, preclinical, and clinical program of highly interactive cancer gene therapy projects.